Over the past decade, a number of experiments have clearly demonstrated that the survival of islet allografts can be significantly prolonged if islets are treated before transplant with agents which are thought to be toxic to antigen-presenting cells. In several experimental models, pretreated islet allografts survive for long periods of time and appear to permanently reverse the diabetic symptoms. Several investigators have noted that animals bearing these long-term islet allografts exhibit a degress of tolerance to donor strain antigens. This tolerance is demonstrated by the fact that these animals do not reject their islet allografts when donor strain spleen cells are administered. In addition, in some cases, animals bearing islet allografts do not reject a subsequent transplant of donor strain skin while they reject third party skin in a normal fashion. Evidence suggests that suppressor T cells may be involved in this tolerance response. The tolerance response to long-term islet allografts is not universally reported nor consistently found in all members of an experimental group. This tolerance response has not been approached in a systematic fashion in an attempt to identify those factors which are required for and/or most influential in inducing tolerance and those factors which inhibit its induction or produce a form of tolerance which is easily abrogated. Consistently reproducible donor-specific tolerance would be of considerable clinical value. It may be used to ensure the survival of existing islet allografts or permit the subsequent transplantation of cryopreserved, untreated donor islets in high enough concentrations to reverse hyperglycemia. This procedure would be especially useful if it could be accomplished using xenogeneic islets. We propose to test a number of variables for their importance in inducing tolerance to long-term islet allografts. We will test islet dosage, the method of islet pretreatment, the source of islet tissue, the duration of engraftment, the transplant site, the diabetic status of the recipient and the degree of elimination of antigen presenting cells from the graft. We will assess the presence of tolerance by testing the ability of 107 donor strain spleen cells to induce rejection of the islet allograft. These studies will lay the foundation for future work in which the limits of tolerance will be tested in an attempt to determine whether a large number of untreated donor strain islets can be successfully transplanted to a tolerant animal to reverse diabetes. Xenogenic tolerance studies are also planned.